Whole-cell voltage-clamp and single channel recording techniques were used to study drug interactions with N-methyl-D-aspartate (NMDA) and non- NMDA receptor-coupled cation and gamma-aminobutyric acid/A (GABA/A) receptor-coupled Cl- channels in cultured hippocampal neurons and with voltage-dependent K+ channels in fibroblasts transfected with K+ channel genes. The aim of this work was to explore new strategies for the rational development of antiepileptic drugs based upon their interaction with neuronal ion channel systems. Work was focused in the following areas: (1) studies on the direct activation of GABA/A receptors by barbiturates; (2) evidence for barbiturate-like actions of felbamate (an antiepileptic dicarbamate) and meprobamate (an anxiolytic dicarbamate); (3) studies demonstrating the failure of felbamate to act as an antagonist of the glycine site on NMDA receptors; (4) evidence for an interaction of the anticonvulsant remacemide with the polyamine site on NMDA receptors; (5) effects of the polyamine toxin argiotoxin 636 on NMDA receptors; (6) mechanism of block of the Kv1.2 K+ channel by aminopyridines and quinine; (7) alaproclate effects on NMDA receptors and the Kv1.2 K+ channel; (8) K+ channel activator (cromakalim and diazoxide) effects on anoxia- and 4-aminopyridine-induced hyperexcitability; and (9) neurosteroid potentiation and inhibition of NMDA receptor responses. Felbamate, a newly approve antiepileptic agent, and the related dicarbamate meprobamate, were found to exhibit barbiturate-like effects on GABA/A receptors, both in their activity as modulators of single GABA/A receptor currents and, in the case of meprobamate, to directly activate the receptor. The low toxicity of felbamate could relate, in part, to its failure to produce this latter effect. Studies were continued on the interaction of remacemide (an anticonvulsant drug currently under clinical investigation) with the NMDA receptor. Remacemide was found to allosterically inhibit NMDA receptor channel opening via an action at the NMDA receptor's polyamine site.